Processes for preparing aromatic ethers

ABSTRACT

The present invention relates to processes for preparing aromatic ether compounds that are modulators of glucose metabolism and therefore useful in the treatment of metabolic disorders such as diabetes and obesity.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Ser. No. 60/642,627, filedJan. 10, 2005, the disclosure of which is incorporated herein byreference in its entirety.

FIELD OF THE INVENTION

The present invention relates to processes for preparing aromatic ethercompounds that are modulators of glucose metabolism and therefore usefulin the treatment of metabolic disorders such as diabetes and obesity.

BACKGROUND OF THE INVENTION

Modulation of G-protein coupled receptors has been well-studied forcontrolling various metabolic disorders. Small molecule modulators ofthe receptor RUP3, a G-protein coupled-receptor described in, forexample, GenBank (see, e.g., accession numbers XM_(—)066873 andAY288416), have been shown to be useful for treating or preventingcertain metabolic disorders. In particular, aromatic ethers and similarcompounds, which are described in U.S. Ser. No. 10/888,747, are shown tobe effective modulators of the RUP3 receptor and are useful in thetreatment of various metabolic-related disorders such as type Idiabetes, type II diabetes, inadequate glucose tolerance, insulinresistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia,hypercholesterolemia, dyslipidemia or syndrome X. The aromatic ethersare also useful in controlling weight gain, controlling food intake, andinducing satiety in mammals. The promising nature of these RUP3modulators in treating or preventing a number of common diseasesevidences a need for more efficient processes of making these compounds.The processes described herein are directed toward this and othercurrent needs.

SUMMARY OF THE INVENTION

The present invention provides processes for preparing compounds ofFormula I:

wherein constituent members are defined herein, comprising reacting acompound of Formula II:

with compound of Formula III:

in the presence of a base, thereby forming the compound of Formula I.

The present invention also provides processes for preparing compounds ofFormula II by:

a) combining a compound of Formula IV:

with a compound of Formula V:

to form a mixture; and

b) adding a base to the mixture, thereby forming the compound of FormulaII.

The present invention further provides bulk samples of the compound ofFormula I or II prepared according to the processes herein.

DETAILED DESCRIPTION

The present invention is directed to processes and intermediates for thepreparation of aromatic ethers that are useful as RUP3 modulators forthe treatment of metabolic disorders such as diabetes and obesity.

Example processes and intermediates of the present invention areprovided below in Scheme I, wherein constituent members of the formulaedepicted therein are defined below.

The present invention provides processes, such as exemplified in SchemeI, involving compounds of Formulas I, II, III, IV, and V, or salt formsthereof, wherein:

L¹ is a leaving group;

L² is a leaving group

X is N or CR⁷;

Y is N or CR⁸;

Z is C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl,C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylthiocarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, C₁₋₂ alkylamino,C₂₋₄ dialkylamino, carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide,carboxy, cyano, C₃₋₇ cycloalkyl, C₄₋₈ diacylamino, C₂₋₆dialkylcarboxamide, C₂₋₄ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₂₋₆ dialkylsulfonylamino, formyl, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkylcarboxamide, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen, aryl, heteroaryl,heterocycloalkyl, hydroxyl, hydroxycarbamimidoyl, hydroxylamino, nitro,or tetrazolyl; wherein said C₁₋₈ alkyl, C₃₋₇ cycloalkyl, andheterocycloalkyl are each optionally substituted with 1, 2, 3 or 4groups selected from C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₇ alkyl,C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₂ alkylamino,C₂₋₄ dialkylamino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino, and nitro;

R¹ is H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, carboxamide, cyano, C₃₋₇cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, or hydroxyl;

R² is —R²², —CR²³R²⁴C(O)—R²², —C(O)CR²³R²⁴—R²², —C(O)—R²²,—CR²³R²⁴C(O)NR²⁵—R²², —NR²⁵C(O)CR²³R²⁴—R²², —C(O)NR²³—R²²,—NR²³C(O)—R²², —C(O)O—R²², —OC(O)—R²², —C(S)—R²², —C(S)NR²³—R²²,—NR²³C(S)—R²², —C(S)O—R²², —OC(S)—R²², —CR²³R²⁴—R²², or —S(O)₂—R²²;

R³ is C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl, orhalogen;

R⁴ is H, C₁₋₈ alkyl or C₃₋₇ cycloalkyl, wherein said C₁₋₈ alkyl isoptionally substituted with C₁₋₄ alkoxy, C₃₋₇ cycloalkyl, or heteroaryl;

R₇ and R₈ are each, independently, H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino,carboxamide, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylsulfonamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, orhydroxyl;

R¹¹ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, arylsulfonyl, carbamimidoyl, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide,guanidinyl, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,heterocycloalkyl, heterocycloalkyl-oxy, heterocycloalkylsulfonyl,heterocycloalkyl-carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl,nitro, C₄₋₇ oxo-cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid,or thiol; and wherein said C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy,C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylsulfonamide, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, arylsulfonyl, carbamimidoyl, C₂₋₆ dialkylamino,heterocycloalkyl, heterocycloalkyl-carbonyl, heteroaryl, phenoxy andphenyl are each optionally substituted with 1 to 5 substituents selectedindependently from C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy,C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,heteroaryl, heterocyclic, hydroxyl, nitro, phenyl, and phosphonooxy,wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are each optionallysubstituted with 1 to 5 substituents selected from C₁₋₄ alkoxy andhydroxy;

R¹², R¹³, R¹⁴, and R¹⁵ are each, independently, H, C₁₋₅ acyl, C₁₋₅acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide,C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy,carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl, or nitro;

R²² is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, orheterocyclic each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, heterocyclic, hydroxyl, hydroxylamino, nitro, phenyl,phenoxy, and sulfonic acid, wherein said C₁₋₇ alkyl, heteroaryl, phenyland phenoxy are each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl,C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide,C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino, and nitro;

R²³, R²⁴ and R²⁵ are each, independently, H or C₁₋₈ alkyl;

n is 0 or 1; and

m is 0, 1, 2, 3, or 4.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention, which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination. All combinations of the embodimentspertaining to the chemical groups represented by the variables (e.g., n,m, R₁, R₂, R₃, R₄, R₁₁, R₁₂, R₁₃, R₁₄, R₁₅, X, Y, Z, etc.) containedwithin the generic chemical formulae described herein [e.g. I, II, III,etc.] and process steps disclosed herein are specifically embraced bythe present invention just as if they were explicitly disclosed, to theextent that such combinations embrace compounds that result in stablecompounds (ie., compounds that can be isolated, characterized and testedfor biological activity). In addition, all subcombinations of thechemical groups listed in the embodiments describing such variables, aswell as all subcombinations of process steps, are also specificallyembraced by the present invention just as if each of such subcombinationof chemical groups and process steps were explicitly disclosed herein.

In some embodiments, L¹ is halo.

In some embodiments, L¹ is Cl.

In some embodiments, L² is halo.

In some embodiments, L² is Cl.

In some embodiments, X is N.

In some embodiments, Y is N.

In some embodiments, both X and Y are N.

In some embodiments, Z is C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, C₁₋₂ alkylamino, C₂₋₄ dialkylamino, carbamimidoyl,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₄₋₈diacylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₂₋₆ dialkylsulfonylamino, formyl, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkylcarboxamide, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen, aryl, heteroaryl,heterocycloalkyl, hydroxyl, hydroxycarbamimidoyl, hydroxylamino, nitro,or tetrazolyl.

In some embodiments, Z is C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₂₋₆ alkynyl, formyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, halogen, hydroxyl, or nitro.

In some embodiments, Z is C₁₋₈ alkyl.

In some embodiments, Z is methyl, ethyl or propyl.

In some embodiments, Z is methyl.

In some embodiments, R¹ is H.

In some embodiments, R² is —C(O)O—R²².

In some embodiments, R² is —C(O)O—R²² and R²² is C₁₋₈ alkyl or C₃₋₇cycloalkyl.

In some embodiments, R² is —C(O)O—R²² and R²² is C₁₋₄ alkyl.

In some embodiments, R² is —C(O)O—R²² and R²² is methyl, ethyl, orprop-1-yl, prop-2-yl.

In some embodiments, R² is —C(O)O—R²² and R²² is prop-2-yl.

In some embodiments, R⁴ is H.

In some embodiments, n is 1.

In some embodiments, m is 0.

In some embodiments, R¹¹ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, arylsulfonyl,carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, guanidinyl, halogen,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocyclic,heterocycloalkyl-oxy, heterocycloalkylsulfonyl,heterocycloalkyl-carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl,nitro, C₄₋₇ oxo-cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid,or thiol.

In some embodiments, R¹¹ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, or C₁₋₄ alkylsulfonyl.

In some embodiments, R¹¹ is C₁₋₄ alkylsulfinyl or C₁₋₄ alkylsulfonyl.

In some embodiments, R¹¹ is C₁₋₄ alkylsulfonyl.

In some embodiments, R¹¹ is methylsulfonyl or ethylsulfonyl.

In some embodiments, R¹¹ is methylsulfonyl.

In some embodiments, R¹², R¹³, R¹⁴, and R¹⁵ are each, independently, H,C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₂₋₆ alkynyl, cyano, halogen,C)₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, hydroxyl, or nitro.

In some embodiments, R¹², R¹³, R¹⁴, and R¹⁵ are each, independently, H,C₁₋₄ alkoxy, C₁₋₈ alkyl, cyano, halogen, hydroxyl, or nitro.

In some embodiments, R¹², R¹³, R¹⁴, and R¹⁵ are each, independently, Hor halogen.

In some embodiments, R¹⁵ is other than H.

In some embodiments, R¹⁵ is halogen.

In some embodiments, R¹⁵ is F.

In some embodiments, R¹², R¹³, and R¹⁴ are each H and R¹⁵ is other thanH.

In some embodiments, R¹¹ is C₁₋₄ alkylsulfonyl; R¹², R¹³, and R¹⁴ areeach H; and R¹⁵ is halogen.

In some embodiments:

X is N;

Y is N;

Z is C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl,C₂₋₆ alkynyl, formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen,hydroxyl, or nitro;

R¹ is H;

R² is —C(O)O—R²²;

R⁴ is H;

R¹¹ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, or C₁₋₄ alkylsulfonyl;

R¹², R¹³, R¹⁴, and R¹⁵ are each, independently, H, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₂₋₆ alkynyl, cyano, halogen, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, hydroxyl, or nitro;

n is 1; and

m is 0 or 1.

In some embodiments:

X is N;

Y is N;

Z is C₁₋₈ alkyl;

R¹ is H;

R² is —C(O)O—R²²;

R⁴ is H;

R¹¹ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, or C₁₋₄ alkylsulfonyl;

R¹², R¹³, and R¹⁴ are each H;

R¹⁵ is C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₂₋₆ alkynyl, cyano,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, hydroxyl, or nitro;

n is 1; and

m is 0 or 1.

In some embodiments:

X is N;

Y is N;

Z is C₁₋₈ alkyl;

R¹ is H;

R² is —C(O)O—R²²;

R⁴ is H;

R¹¹ is C₁₋₄ alkylsulfinyl or C₁₋₄ alkylsulfonyl;

R¹², R¹³, and R¹⁴ are each H;

R¹⁵ is C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₂₋₆ alkynyl, cyano,halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, hydroxyl, or nitro;

R²² is C₁₋₄ alkyl;

n is 1; and

m is 0.

In some embodiments:

X is N;

Y is N;

Z is methyl;

R¹ is H;

R² is —C(O)O—R²²;

R⁴ is H;

R¹¹ is methylsulfonyl;

R¹², R¹³, and R¹⁴ are each H;

R¹⁵ is F;

R²² is prop-2-yl;

n is 1; and

-   m is 0.

In some embodiments, the present invention provides a process forpreparing a compound of Formula I:

by reacting a compound of Formula II:

with compound of Formula III:

in the presence of a base, thereby forming the compound of Formula I.

The reacting of II with III can be further carried out in the presenceof a salt, such as a tetrasubstituted ammonium salt or an iodide salt. Atetrasubstituted ammonium salt includes a salt of formula [N(R)₄][X¹];where X¹ is any monoanion such as fluoride, chloride, bromide, iodide,and the like, and each R is, independently, C₁₋₈ alkyl, aryl, arylalkyl,cycloalkyl, cycloalkylalkyl, heteroaryl, heteroarylalkyl, heterocyclic,or heterocyclic alkyl, each of which can be optionally substituted byhalo, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy, or C₁₋₄ haloalkoxy. Insome embodiments, the tetrasubstituted ammonium salt is a tetra(C₁₋₈alkyl)ammonium salt. In further embodiments, the tetrasubstitutedammonium salt is a tetrabutylammonium salt. In further embodiments, thetetrasubstituted ammonium salt is a halide salt. In further embodiments,the tetrasubstituted ammonium salt is an iodide salt. In furtherembodiments, the tetrasubstituted ammonium salt is tetrabutylammoniumiodide. In further embodiments, the tetrasubstituted ammonium salt is afluorine salt. In further embodiments, the tetrasubstituted ammoniumsalt is tetrabutylammonium fluoride [(CH₃CH₂CH₂CH₂)₄NF].

The reacting of II with III can be further carried out in the presenceof a salt, such as an alkali metal halide salt. Alkali metal halidesalts are known in the art and include salts of formula M-Halide,wherein M is an alkali metal and halide is F, Cl, Br, and I. Examples ofan alkali metal halide salt include, for example, NaF, NaCl, NaBr, NaI,KF, KCl, KBr, KI, CsF, CsCl, CsBr, CsI, and the like.

In the reacting of II with III, the base can be any that is routinelyused in the art for similar coupling reactions. In some embodiments, thebase is an alkali metal amide, alkali metal hydride, alkali metalcarbonate, or an alkali metal hydrogencarbonate. In further embodiments,the base is an alkali metal carbonate. In yet a further embodiment, thebase is K₂CO₃.

In some embodiments, the reacting of II with III can be carried out atelevated temperature. For example, the reaction mixture can be heated toa temperature of about 100 to about 150, about 120 to about 140, orabout 130 to about 135° C.

In some embodiments, the reacting of II with III is carried out in asolvent. Suitable solvents include, for example polar solvents orsolvents having a boiling point above about 100° C. Example polarsolvents include dimethylsulfoxide (DMSO), dimethylformamide (DMF),dimethylacetate (DMA), N-methylpyrrolidine (NMP), acetonitrile,propionitrile, and the like. Example high boiling solvents include DMSO,DMF, DMA, and the like. In some embodiments, the solvent includes DMSO.

In some embodiments, the reacting of II and III is carried out where themolar ratio of the compound of Formula II to Formula III is about 1:1.In some embodiments, the compound of Formula II is provided in slightmolar excess relative to the amount of compound of Formula III. Infurther embodiments, the molar ratio of base to amount of compound ofFormula III is about 2:1 to about 1:1, about 1.3:1 to about 1.1:1, orabout 1.2:1. In yet further embodiments, the molar ratio oftetrasubstituted ammonium salt to amount of compound of Formula III isabout 1:1 to about 0.1:1, about 0.8:1 to about 0.5:1, or about 0.7:1 toabout 0.6:1.

The compound Formula II can be prepared by:

a) combining a compound of Formula IV:

with a compound of Formula V:

to form a mixture; and

b) adding a base to the mixture, thereby forming the compound of FormulaII.

The base which is added to the mixture of IV and V can be any suitablebase including, for example, C₁₋₆ alkoxide salts, alkali metal amides,alkali metal hydrides, alkali metal carbonates, or alkali metalhydrogencarbonates. In some embodiments, the base is a C₁₋₆ alkoxidesalt such as an alkali salt of t-butoxide. In some embodiments, the baseis potassium t-butoxide. Base can be optionally added in one or moreportions such as, for example, two portions.

In some embodiments, the combining of IV and V as well as the addingstep are carried out in a solvent. Example suitable solvents includeether solvents such as dimethoxymethane, tetrahydrofuran, 1,3-dioxane,1,4-dioxane, furan, diethyl ether, ethylene glycol dimethyl ether,ethylene glycol diethyl ether, diethylene glycol dimethyl ether,diethylene glycol diethyl ether, triethylene glycol dimethyl ether,anisole, or t-butyl methyl ether. In some embodiments, the solventincludes tetrahydrofuran. Other suitable solvents include DMF, DMA, NMP,DMSO, acetonitrile and propionitrile.

The adding of base can be optionally carried out at reduced temperature.For example, the addition can be carried out at a temperature belowabout 25, below about 15, below about 10, below about 5, or below about0° C.

In some embodiments, the molar ratio of compound IV to compound V isabout 1:1. In further embodiments, the molar ratio of compound IV tocompound V to base is about 1:1:1. In some embodiments, the molar ratioof base to compound V is about 1.02:1 to about 0.90:1 or about 1:1 toabout 0.96:1.

The compounds of Formulas III, IV, and V can be prepared according toroutine methods in the art. Example preparations of these compounds areprovided such in U.S. application Ser. No. 10/888,747, which isincorporated herein by reference in its entirety.

While routine isolation and purification procedures can yieldsubstantially pure preparations (e.g., bulk samples) of the compound ofFormula I, impurities which are characteristic of the proceduresdescribed herein can occasionally persist. For example, in thepreparation of compounds of Formula II, compounds of Formula IIa canoptionally be present as byproducts which optionally can be carried overto the preparation of Formula I if the byproduct is present in startingmaterial II.

In some embodiments, bulk samples of Formula II made by the processesdescribed herein can contain a detectable amount of compound of FormulaIIa. The amount of compound of Formula IIa in preparations of Formula IIcan be, for example, less than about 5%, less than about 3%, less thanabout 2%, less than about 1%, less than about 0.5%, less than about0.2%, less than about 0.1%, less than about 0.05%, less than about0.02%, or less than about 0.01% by weight.

In some embodiments, bulk samples of Formula I made by the processesdescribed herein can contain a detectable amount of compound of FormulaIIa. The amount of compound of Formula IIa in preparations of Formula Ican be, for example, less than about 5%, less than about 3%, less thanabout 2%, less than about 1%, less than about 0.5%, less than about0.2%, less than about 0.1%, less than about 0.05%, less than about0.02%, or less than about 0.01% by weight.

In some embodiments, the byproduct is compound of Formula IIb:

The compound of Formula IIa and other byproducts can be detected andquantified by routine methods including, for example, proton nuclearmagnetic resonance, high performance liquid chromatography, massspectrometry, and the like. The amount of compound of Formula IIa andother byproducts in bulk samples prepared according to the processesherein can be reduced or substantially eliminated by routine methodssuch as recrystallization or chromatography techniques.

The term “bulk sample” is used herein consistently with its meaning inthe art which, for example, refers to an amount of product preparedaccording to a given process or procedure. Bulk samples can be any size,but typically range from 1 mg on upward to several thousands ofkilograms or more.

It is appreciated that certain features of the invention, which are, forclarity, described in the context of separate embodiments, may also beprovided in combination in a single embodiment. Conversely, variousfeatures of the invention which are, for brevity, described in thecontext of a single embodiment, may also be provided separately or inany suitable subcombination.

The term “C_(i-j)” denotes the number of carbon atoms in the moiety towhich the term refers. For example, C₁₋₈ alkyl (where i is 1 and j is 8)refers to an alkyl group having 1 (C₁), 2 (C₂), 3 (C₃), 4 (C₄), 5 (C₅),6 (C₆), 7 (C₇), or 8 (C₈) carbon atoms.

The term “acyl” denotes a carbonyl (C═O) substituted by an alkylradical, wherein the definition of alkyl has the same definition asdescribed herein. Some examples include, but are not limited to, acetyl,propionyl, n-butanoyl, iso-butanoyl, sec-butanoyl, t-butanoyl (i.e.,pivaloyl), pentanoyl and the like.

The term “acyloxy” denotes —O— substituted by an acyl radical, whereinacyl has the same definition has described herein. Some examples includebut are not limited to acetyloxy, propionyloxy, butanoyloxy,iso-butanoyloxy, sec-butanoyloxy, t-butanoyloxy and the like.

The term “acylsulfonamide” refers to a sulfonamide substituted by acylon the sulfonamide N-atom, wherein the definitions for acyl andsulfonamide have the same meaning as described herein, and anacylsulfonamide can be represented by the following formula:

Some embodiments of the present invention include C₁₋₅ acylsulfonamide,C₁₋₄ acylsulfonamide, C₁₋₃ acylsulfonamide, or C₁₋₂ acylsulfonamide.Examples of acylsulfonamides include, but are not limited to,acetylsulfamoyl [—S(═O)₂NHC(═O)Me], propionylsulfamoyl[—S(═O)₂NHC(═O)Et], isobutyrylsulfamoyl, butyrylsulfamoyl,2-methyl-butyrylsulfamoyl, 3-methyl-butyrylsulfamoyl,2,2-dimethyl-propionylsulfamoyl, pentanoylsulfamoyl,2-methyl-pentanoylsulfamoyl, 3-methyl-pentanoylsulfamoyl,4-methyl-pentanoylsulfamoyl, and the like.

The term “alkenyl” denotes an alkyl radical containing having at leastone carbon-carbon double bond. In some embodiments, the alkenyl group isC₂₋₆ alkenyl, C₂₋₅ alkenyl, C₂₋₄ alkenyl, C₂₋₃ alkenyl or C₂ alkenyl.Both E and Z isomers are embraced by the term “alkenyl.” Furthermore,the term “alkenyl” includes groups with 1, 2, 3, 4 or more double bonds.Accordingly, if more than one double bond is present then the bonds maybe all E or Z or a mixtures of E and Z. Examples of an alkenyl includevinyl, allyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl,2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexanyl, 2,4-hexadienyl and the like.

The term “alkoxy” as used herein denotes a radical alkyl, as definedherein, attached directly to an oxygen atom. Examples include methoxy,ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, iso-butoxy,sec-butoxy and the like.

The term “alkyl” denotes a straight or branched hydrocarbon radical. Insome embodiments, the alkyl group contains 1 to 8 carbons, 1 to 7carbons, 1 to 6 carbons, 1 to 5 carbons, 1 to 4 carbons, 1 to 3 carbons,1 or 2 carbons. Examples of alkyl groups include, but are not limitedto, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl,t-butyl, pentyl, iso-pentyl, t-pentyl, neo-pentyl, 1-methylbutyl [i.e.,—CH(CH₃)CH₂CH₂CH₃], 2-methylbutyl [i.e., —CH₂CH(CH₃)CH₂CH₃], n-hexyl andthe like.

The term “alkylcarboxamido” or “alkylcarboxamide” denotes a single alkylgroup attached to the nitrogen or carbon of an amide group, whereinalkyl has the same definition as found herein. The alkylcarboxamide maybe represented by the following:

Examples include, but are not limited to, N-methylcarboxamide,N-ethylcarboxamide, N-n-propylcarboxamide, N-iso-propylcarboxamide,N-n-butylcarboxamide, N-sec-butylcarboxamide, N-iso-butylcarboxamide,N-t-butylcarboxamide and the like.

The term “alkylene” refers to a divalent alkyl group. In someembodiments, alkylene refers to, for example, —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, and the like. In some embodiments, alkylene refers to —CH—,—CHCH₂—, —CHCH₂CH₂—, and the like wherein these examples relategenerally to “A”.

The term “alkylsulfinyl” denotes —S(O)— substituted by alkyl, whereinthe alkyl radical has the same definition as described herein. Examplesinclude, but not limited to, methylsulfinyl, ethylsulfinyl,n-propylsulfinyl, iso-propylsulfinyl, n-butylsulfinyl,sec-butylsulfinyl, iso-butylsulfinyl, t-butyl, and the like.

The term “alkylsulfonamide” refers to the groups

wherein alkyl has the same definition as described herein.

The term “alkylsulfonyl” denotes —S(O)₂— substituted by alkyl, whereinthe alkyl radical has the same definition as described herein. Examplesinclude, but are not limited to, methylsulfonyl, ethylsulfonyl,n-propylsulfonyl, iso-propylsulfonyl, n-butylsulfonyl,sec-butylsulfonyl, iso-butylsulfonyl, t-butyl, and the like.

The term “alkylthio” denotes —S— substituted by alkyl, wherein the alkylradical has the same definition as described herein. Examples include,but not limited to, methylsulfanyl (i.e., CH₃S—), ethylsulfanyl,n-propylsulfanyl, iso-propylsulfanyl, n-butylsulfanyl,sec-butylsulfanyl, iso-butylsulfanyl, t-butyl, and the like.

The term “alkylthiocarboxamide” denotes a thioamide of the followingformulae:

wherein alkyl has the same definition as described herein.

The term “alkylthioureyl” denotes the group of the formula: —NC(S)N—wherein one or both of the nitrogens are substituted with the same ordifferent alkyl groups, and alkyl has the same definition as describedherein. Examples of an alkylthioureyl include, but are not limited to,CH₃NHC(S)NH—, NH₂C(S)NCH₃—, (CH₃)₂N(S)NH—, (CH₃)₂N(S)NH—,(CH₃)₂N(S)NCH₃—, CH₃CH₂NHC(S)NH—, CH₃CH₂NHC(S)NCH₃—, and the like.

The term “alkylureyl” denotes the group of the formula: —NC(O)N— whereinone are both of the nitrogens are substituted with the same or differentalkyl group, wherein alkyl has the same definition as described herein.Examples of an alkylureyl include, but not limited to, CH₃NHC(O)NH—,NH₂C(O)NCH₃—, (CH₃)₂N(O)NH—, (CH₃)₂N(O)NH—, (CH₃)₂N(O)NCH₃—,CH₃CH₂NHC(O)NH—, CH₃CH₂NHC(O)NCH₃—, and the like.

The term “alkynyl” denotes an alkyl group having at least onecarbon-carbon triple bond. In some embodiments, the alkynyl group has 2to 8 carbons, 2 to 7 carbons, 2 to 6 carbons, 2 to 5 carbons, 2 to 4carbons, 2 to 3 carbons, or 2 carbons. Examples of alkynyl groupsinclude, but are not limited to, ethynyl, 1-propynyl, 2-propynyl,1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl,4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl andthe like. Additionally, an alkynyl group can have 1, 2, 3, 4 or moretriple bonds, forming for example, di- and tri-ynes.

The term “amino” denotes the group —NH₂.

The term “alkylamino” denotes amino substituted by alkyl, wherein thealkyl radical has the same meaning as described herein. Some examplesinclude, but not limited to, methylamino, ethylamino, n-propylamino,iso-propylamino, n-butylamino, sec-butylamino, iso-butylamino,t-butylamino, and the like.

The term “aryl” denotes monocyclic or polycyclic aromatic hydrocarbonssuch as, for example, phenyl, naphthyl, anthracenyl, phenanthrenyl,indanyl, indenyl, and the like. In some embodiments, aryl groups havefrom 6 to about 20 carbon atoms.

The term “arylalkyl” denotes alkyl substituted with an aryl group.Examples of an “arylalkyl” include benzyl, phenethylene and the like.

The term “arylcarboxamido” denotes an amide group substituted by an arylgroup on the N-atom, wherein aryl has the same definition as foundherein. An example is N-phenylcarboxamide.

The term “arylureyl” denotes the group —NC(O)N— where one of thenitrogens are substituted with an aryl.

The term “benzyl” denotes the group —CH₂C₆H₅.

The term “carbamimidoyl” refers to a group of the following chemicalformula:

and in some embodiments, one or both hydrogens are replaced with anothergroup. For example, one hydrogen can be replaced with a hydroxyl groupto give a N-hydroxycarbamimidoyl group, or one hydrogen can be replacedwith an alkyl group to give N-methylcarbamimidoyl, N-ethylcarbamimidoyl,N-propylcarbamimidoyl, N-butylcarbamimidoyl, and the like.

The term “carboalkoxy” refers to an alkyl ester of a carboxylic acid,wherein the alkyl group is as defined herein. Examples include, but notlimited to, carbomethoxy, carboethoxy, carbopropoxy, carboisopropoxy,carbobutoxy, carbo-sec-butoxy, carbo-iso-butoxy, carbo-t-butoxy,carbo-n-pentoxy, carbo-iso-pentoxy, carbo-t-pentoxy, carbo-neo-pentoxy,carbo-n-hexyloxy, and the like.

The term “carboxamide” refers to the group —CONH₂.

The term “carboxy” or “carboxyl” denotes the group —CO₂H; also referredto as a carboxylic acid group.

The term “cyano” denotes the group —CN.

The term “cycloalkenyl” denotes a non-aromatic ring radical containing 3to 6 ring carbons and at least one double bond; some embodiments contain3 to 5 carbons; some embodiments contain 3 to 4 carbons. Examplesinclude cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentenyl,cyclohexenyl, and the like.

The term “cycloalkyl” denotes a saturated, cyclic hydrocarboncontaining, for example, 3 to 14, 1 to 10, 3 to 8, 3 to 7, 3 to 6, 3 to5, or 3 to 4 carbons. Examples include cyclopropyl, cyclobutyl,cyclopentyl, cyclopenyl, cyclohexyl, cycloheptyl and the like.

The term “cycloalkylalkyl” denotes an alkyl group substituted by acycloalkyl group.

The term “cycloalkylene” refers to a divalent cycloalkyl radical. Insome embodiments, the two bonding groups are on the same carbon, forexample:

In some embodiments, the two bonding groups are on different carbons.

The term “diacylamino” denotes an amino group substituted with two acylgroups, wherein the acyl groups may be the same or different, such as:

Examples of diacylamino groups include, but limited to, diacetylamino,dipropionylamino, acetylpropionylamino and the like.

The term “dialkylamino” denotes an amino group substituted with two ofthe same or different alkyl radicals, wherein alkyl has the samedefinition as described herein. Some examples include, but not limitedto, dimethylamino, methylethylamino, diethylamino, methylpropylamino,methylisopropylamino, ethylpropylamino, ethylisopropylamino,dipropylamino, propylisopropylamino and the like.

The term “dialkylcarboxamido” or “dialkylcarboxamide” denotes an amidesubstituted by two alkyl radicals, that are the same or different.Dialkylcarboxamidos can be represented by the following groups:

Examples of dialkylcarboxamides include, but are not limited to,N,N-dimethylcarboxamide, N-methyl-N-ethylcarboxamide,N,N-diethylcarboxamide, N-methyl-N-isopropylcarboxamide, and the like.

The term “dialkylsulfonamide” refers to one of the following groupsshown below:

Examples include, but are not limited to, methyl, ethyl, n-propyl,isopropyl, and the like.

The term “dialkylthiocarboxamido” or “dialkylthiocarboxamide” denotes athioamide substituted by two alkyl radicals, that are the same ordifferent, wherein alkyl has the same definition as described herein.Example dialkylthiocarboxamido groups can be represented by thefollowing groups:

Examples of dialkylthiocarboxamides include, but are not limited to,N,N-dimethylthiocarboxamide, N-methyl-N-ethylthiocarboxamide and thelike.

The term “dialkylsulfonylamino” refers to an amino group substitutedwith two alkylsulfonyl groups as defined herein.

The term “ethynylene” refers to —C≡C—.

The term “formyl” refers to the group —CHO.

The term “guanidine” refers to a group of the following chemicalformula:

The term “haloalkoxy” denotes —O— substituted by haloalkyl. Examplesinclude, but are not limited to, difluoromethoxy, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluoroethoxy, and the like.

The term “haloalkyl” denotes an alkyl group, as defined herein, whereinthe alkyl is substituted with one or more halogens. Examples ofhaloalkyl groups include, but are not limited to, fluoromethyl,difluoromethyl, trifluoromethyl, chlorodifluoromethyl,2,2,2-trifluoroethyl, pentafluoroethyl and the like.

The term “haloalkylcarboxamide” denotes an alkylcarboxamide group,defined herein, substituted with one or more halogens.

The term “haloalkylsulfinyl” denotes sulfoxide —S(O)— substituted by ahaloalkyl radical, wherein the haloalkyl radical has the same definitionas described herein. Examples include, but are not limited to,trifluoromethylsulfinyl, 2,2,2-trifluoroethylsulfinyl,2,2-difluoroethylsulfinyl and the like.

The term “haloalkylsulfonyl” denotes —S(O)₂— substituted by a haloalkylradical, wherein haloalkyl has the same definition as described herein.Examples include, but not limited to, trifluoromethylsulfonyl,2,2,2-trifluoroethylsulfonyl, 2,2-difluoroethylsulfonyl and the like.

The term “haloalkylthio” denotes —S— substituted by a haloalkyl radical,wherein the haloalkyl has the same meaning as described herein. Examplesinclude, but not limited to, trifluoromethylthio (i.e., CF₃S—),1,1-difluoroethylthio, 2,2,2-trifluoroethylthio and the like.

The term “halogen” or “halo” denotes to a fluoro, chloro, bromo or iodogroup.

The term “heteroalkylene” refers to alkylene interrupted or appended bya heteroatom-containing group selected from O, S, S(O), S(O)₂ and NH.Some examples include, but not limited to, the groups of the followingformulae:

and the like.

The term “heteroaryl” denotes an aromatic ring system that may be asingle ring, two fused rings or three fused rings wherein at least onering carbon is a heteroatom selected from, but not limited to, the groupconsisting of O, S and N, wherein the N can be optionally substitutedwith H, O, C₁₋₄ acyl or C₁₋₄ alkyl. Examples of heteroaryl groupsinclude, but are not limited to, pyridyl, benzofuranyl, pyrazinyl,pyridazinyl, pyrimidinyl, triazinyl, quinoline, benzoxazole,benzothiazole, 1H-benzimidazole, isoquinoline, quinazoline, quinoxalineand the like. In some embodiments, the heteroatom is O, S, NH, examplesinclude, but not limited to, pyrrole, indole, and the like.

The term “heteroarylalkyl” denotes an alkyl group substituted by aheteroaryl group.

The term “heterocyclic” denotes a non-aromatic, cyclic hydrocarbon(i.e., cycloalkyl or cycloalkenyl as defined herein) wherein one or more(e.g., one, two or three) ring carbons are replaced by a heteroatomselected from, but not limited to, the group consisting of O, S, N,wherein the N can be optionally substituted with H, O, C₁₋₄ acyl or C₁₋₄alkyl, and ring carbon atoms are optionally substituted with oxo or asulfido thus forming a carbonyl or thiocarbonyl group. The heterocyclicgroup can be a 3-, 4-, 5-, 6- or 7-membered ring. Examples of aheterocyclic group include but not limited to aziridin-1-yl,aziridin-2-yl, azetidin-1-yl, azetidin-2-yl, azetidin-3-yl,piperidin-1-yl, piperidin-4-yl, morpholin-4-yl, piperzin-1-yl,piperzin-4-yl, pyrrolidin-1-yl, pyrrolidin-3-yl, [1,3]-dioxolan-2-yl andthe like.

The term, “heterocyclicalkyl” denotes an alkyl group substituted by aheterocyclic group.

The term “heterocyclic-carbonyl” denotes a carbonyl group substituted bya heterocyclic group, as defined herein. In some embodiments, a ringnitrogen of the heterocyclic group is bonded to the carbonyl groupforming an amide. Examples include, but are not limited to,

and the like.In some embodiments, a ring carbon is bonded to the carbonyl groupforming a ketone group. Examples include, but are not limited to,

and the like.

The term “heterocyclic-oxy” refers —O— substituted by a heterocyclicgroup, as defined herein. Examples include the following:

and the like.

The term “heterocyclicsulfonyl” denotes SO₂ substituted with aheterocyclic group having a ring nitrogen, where the ring nitrogen isbonded directly to an SO₂ group forming an sulfonamide. Examplesinclude, but not limited to,

and the like.

The term “hydroxyl” refers to the group —OH.

The term “hydroxylamino” refers to the group —NHOH.

The term “nitro” refers to the group —NO₂.

The term “oxo-cycloalkyl” refers to cycloalkyl, as defined herein,wherein one of the ring carbons is replaced with a carbonyl. Examples ofoxo-cycloalkyl include, but are not limited to, 2-oxo-cyclobutyl,3-oxo-cyclobutyl, 3-oxo-cyclopentyl, 4-oxo-cyclohexyl, and the like andrepresented by the following structures respectively:

The term “perfluoroalkyl” denotes the group of the formula—C_(n)F_(2n+1). Examples of perfluoroalkyls include CF₃, CF₂CF₃,CF₂CF₂CF₃, CF(CF₃)₂, CF₂CF₂CF₂CF₃, CF₂CF(CF₃)₂, CF(CF₃)CF₂CF₃ and thelike.

The term “phenoxy” refers to the group C₆H₅O—.

The term “phenyl” refers to the group C₆H₅—.

The term “phosphonooxy” refers to a group with the following chemicalstructure:

The term “sulfonamide” refers to the group —SO₂NH₂.

The term “sulfonic acid” refers to the group —SO₃H.

The term “tetrazolyl” refers to the five membered heteroaryl of thefollowing formulae:

In some embodiments, the tetrazolyl group is further substituted ateither the 1 or 5 position, resepectively, with a group selected fromthe group consisting of alkyl, haloalkyl and alkoxy.

The term “thiol” denotes the group —SH.

As used herein, the term “reacting” is used as known in the art andgenerally refers to the bringing together of chemical reagents in such amanner so as to allow their interaction at the molecular level toachieve a chemical or physical transformation of at least one chemicalreagent.

As used herein, the term “substituted” refers to the replacement of ahydrogen moiety with a non-hydrogen moiety in a molecule or group.

For compounds in which a variable appears more than once, each variablecan be a different moiety selected from the Markush group defining thevariable. For example, where a structure is described having two Rgroups that are simultaneously present on the same compound; the two Rgroups can represent different moieties selected from the Markush groupdefined for R. In another example, when an optionally multiplesubstituent is designated in the form:

then it is understood that substituent R can occur s number of times onthe ring, and R can be a different moiety at each occurrence.

As used herein, the term “leaving group” refers to a moiety that can bedisplaced by another moiety, such as by nucleophilic attack, during achemical reaction. Leaving groups are well known in the art and include,for example, halogen including chloro, bromo, iodo, and the like.

The processes described herein can be monitored according to anysuitable method known in the art. For example, product formation can bemonitored by spectroscopic means, such as nuclear magnetic resonancespectroscopy (e.g., ¹H or ¹³C) infrared spectroscopy, spectrophotometry(e.g., UV-visible), or mass spectrometry, or by chromatography such ashigh performance liquid chromatography (HPLC) or thin layerchromatography.

In some embodiments, preparation of compounds can involve the protectionand deprotection of various chemical groups. The need for protection anddeprotection, and the selection of appropriate protecting groups can bereadily determined by one skilled in the art. The chemistry ofprotecting groups can be found, for example, in Greene and Wuts, et al.,Protective Groups in Organic Synthesis, 3rd. Ed., Wiley & Sons, 1999,which is incorporated herein by reference in its entirety.

The reactions of the processes described herein can be carried out insuitable solvents which can be readily selected by one of skill in theart of organic synthesis. Suitable solvents can be substantiallynonreactive with the starting materials (reactants), the intermediates,or products at the temperatures at which the reactions are carried out,e.g., temperatures which can range from the solvent's freezingtemperature to the solvent's boiling temperature. A given reaction canbe carried out in one solvent or a mixture of more than one solvent.Depending on the particular reaction step, suitable solvents for aparticular reaction step can be selected. In some embodiments, reactionscan be carried out in the absence of solvent, such as when at least oneof the reagents is a liquid or gas.

Suitable solvents can include halogenated solvents such as carbontetrachloride, bromodichloromethane, dibromochloromethane, bromoform,chloroform, bromochloromethane, dibromomethane, butyl chloride,dichloromethane, tetrachloroethylene, trichloroethylene,1,1,1-trichloroethane, 1,1,2-trichloroethane, 1,1-dichloroethane,2-chloropropane, hexafluorobenzene, 1,2,4-trichlorobenzene,o-dichlorobenzene, chlorobenzene, fluorobenzene, fluorotrichloromethane,chlorotrifluoromethane, bromotrifluoromethane, carbon tetrafluoride,dichlorofluoromethane, chlorodifluoromethane, trifluoromethane,1,2-dichlorotetrafluorethane and hexafluoroethane.

Suitable ether solvents include: dimethoxymethane, tetrahydrofuran,1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene glycol dimethylether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether,diethylene glycol diethyl ether, triethylene glycol dimethyl ether,anisole, or t-butyl methyl ether.

Suitable protic solvents can include, by way of example and withoutlimitation, water, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol,2,2,2-trifluoroethanol, ethylene glycol, 1-propanol, 2-propanol,2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butylalcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol,neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethylether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol,phenol, or glycerol.

Suitable aprotic solvents can include, by way of example and withoutlimitation, tetrahydrofuran (THF), dimethylformamide (DMF),dimethylacetamide (DMAC),1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU),1,3-dimethyl-2-imidazolidinone (DMI), N-methylpyrrolidinone (NMP),formamide, N-methylacetamide, N-methylformamide, acetonitrile, dimethylsulfoxide, propionitrile, ethyl formate, methyl acetate,hexachloroacetone, acetone, ethyl methyl ketone, ethyl acetate,sulfolane, N,N-dimethylpropionamide, tetramethylurea, nitromethane,nitrobenzene, or hexamethylphosphoramide.

Suitable hydrocarbon solvents include benzene, cyclohexane, pentane,hexane, toluene, cycloheptane, methylcyclohexane, heptane, ethylbenzene,m-, o-, or p-xylene, octane, indane, nonane, or naphthalene.

Supercritical carbon dioxide can also be used as a solvent.

The reactions of the processes described herein can be carried out atappropriate temperatures which can be readily determined by the skilledartisan. Reaction temperatures will depend on, for example, the meltingand boiling points of the reagents and solvent, if present; thethermodynamics of the reaction (e.g., vigorously exothermic reactionsmay need to be carried out at reduced temperatures); and the kinetics ofthe reaction (e.g., a high activation energy barrier may need elevatedtemperatures). “Elevated temperature” refers to temperatures above roomtemperature (about 25° C.) and “reduced temperature” refers totemperatures below room temperature.

The reactions of the processes described herein can be carried out inair or under an inert atomosphere. Typically, reactions containingreagents or products that are substantially reactive with air can becarried out using air-sensitive synthetic techniques that are well knownto the skilled artisan.

In some embodiments, preparation of compounds can involve the additionof acids or bases to effect, for example, catalysis of a desiredreaction or formation of salt forms such as acid addition salts.

Example acids can be inorganic or organic acids. Inorganic acids includehydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, andnitric acid. Organic acids include formic acid, acetic acid, propionicacid, butanoic acid, methanesulfonic acid, p-toluene sulfonic acid,benzenesulfonic acid, trifluoroacetic acid, propiolic acid, butyricacid, 2-butynoic acid, vinyl acetic acid, pentanoic acid, hexanoic acid,heptanoic acid, octanoic acid, nonanoic acid and decanoic acid.

Example bases include lithium hydroxide, sodium hydroxide, potassiumhydroxide, lithium carbonate, sodium carbonate, and potassium carbonate.Some example strong bases include, but are not limited to, hydroxide,alkoxides, metal amides, metal hydrides, metal dialkylamides andarylamines, wherein; alkoxides include lithium, sodium and potassiumsalts of methyl, ethyl and t-butyl oxides; metal amides include sodiumamide, potassium amide and lithium amide; metal hydrides include sodiumhydride, potassium hydride and lithium hydride; and metal dialkylamidesinclude sodium and potassium salts of methyl, ethyl, n-propyl, i-propyl,n-butyl, t-butyl, trimethylsilyl and cyclohexyl substituted amides.

The compounds described herein can be asymmetric (e.g., having one ormore stereocenters). All stereoisomers, such as enantiomers anddiastereomers, are intended unless otherwise indicated. Compounds of thepresent invention that contain asymmetrically substituted carbon atomscan be isolated in optically active or racemic forms. Methods on how toprepare optically active forms from optically active starting materialsare known in the art, such as by resolution of racemic mixtures or bystereoselective synthesis.

The processes described herein can be stereoselective such that anygiven reaction starting with one or more chiral reagents enriched in onestereoisomer forms a product that is also enriched in one stereoisomer.The reaction can be conducted such that the product of the reactionsubstantially retains one or more chiral centers present in the startingmaterials. The reaction can also be conducted such that the product ofthe reaction contains a chiral center that is substantially invertedrelative to a corresponding chiral center present in the startingmaterials.

Resolution of racemic mixtures of compounds can be carried out by any ofnumerous methods known in the art. An example method includes fractionalrecrystallizaion using a “chiral resolving acid” which is an opticallyactive, salt-forming organic acid. Suitable resolving agents forfractional recrystallization methods are, for example, optically activeacids, such as the D and L forms of tartaric acid, diacetyltartaricacid, dibenzoyltartaric acid, mandelic acid, malic acid, lactic acid orthe various optically active camphorsulfonic acids such asα-camphorsulfonic acid. Other resolving agents suitable for fractionalcrystallization methods include stereoisomerically pure forms ofα-methylbenzylamine (e.g., S and R forms, or diastereomerically pureforms), 2-phenylglycinol, norephedrine, ephedrine, N-methylephedrine,cyclohexylethylamine, 1,2-diaminocyclohexane, and the like.

Resolution of racemic mixtures can also be carried out by elution on acolumn packed with an optically active resolving agent (e.g.,dinitrobenzoylphenylglycine). Suitable elution solvent composition canbe determined by one skilled in the art.

Compounds of the invention can also include all isotopes of atomsoccurring in the intermediates or final compounds. Isotopes includethose atoms having the same atomic number but different mass numbers.For example, isotopes of hydrogen include tritium and deuterium.

Compounds of the invention can also include tautomeric forms, such asketo-enol tautomers. Tautomeric forms can be in equilibrium orsterically locked into one form by appropriate substitution.

The present invention also includes salt forms of the compoundsdescribed herein. Examples of salts (or salt forms) include, but are notlimited to, mineral or organic acid salts of basic residues such asamines, alkali or organic salts of acidic residues such as carboxylicacids, and the like. Generally, the salt forms can be prepared byreacting the free base or acid with stoichiometric amounts or with anexcess of the desired salt-forming inorganic or organic acid or base ina suitable solvent or various combinations of solvents. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosureof which is hereby incorporated by reference in its entirety.

Upon carrying out preparation of compounds according to the processesdescribed herein, the usual isolation and purification operations suchas concentration, filtration, extraction, solid-phase extraction,recrystallization, chromatography, and the like may be used, to isolatethe desired products.

The invention will be described in greater detail by way of specificexamples. The following examples are offered for illustrative purposes,and are not intended to limit the invention in any manner. Those ofskill in the art will readily recognize a variety of noncriticalparameters which can be changed or modified to yield essentially thesame results.

EXAMPLES Example 1 Preparation of 4,6-Dichloro-5-MethylpyrimidineIntermediate (1)

A solution of diethyl-methylmalonate (0.11 mol) in methanol (100 mL) wasadded to a saturated solution of ammonia in methanol (7N, 200 mL)containing sodium (0.2 g, 0.08 eq) at 0° C. The mixture was allowed tostand in a stoppered flask at room temperature 2-3 days. The separateddiamide was collected as a white solid by filtration, washed by methanoland dried.

To a solution of Na (1.03 mol, 1.2 eq) in ethanol (2 L) was addeddiamide from Step 1 (0.86 mol, 1 eq) as a solid. The mixture was heatedto reflux and formamide (3.4 mol, 4 eq) was slowly added, the resultingmixture was refluxed for an additional 3 h. The desired compound wasfiltered at room temperature as a white solid (as a sodium salt), washedby ethanol and dried.

The above solid was dissolved in water, which was acidified to pH=5using concentrated solution of HCl (12 N). The mixture was stirred at 5°C. for 30 min. The white solid was filtered and dried under vacuum (60%yield).

To a mixture of pyrimidine derivative from Step 2 (0.38 mol, 1 eq) inPOCl₃ (1.9 mol, 174 mL) was slowly added DMF (exothermic reaction, 0.152mol, 11.7 mL). The resulting mixture was heated to reflux for 3 h,cooled to room temperature and poured into ice/water. The resultingwhite solid was filtered, washed with water and dried under vacuum (90%yield) to give 4,6-dichloro-5-methylpyrimidine (1).

Example 2 Preparation of 4-Hydroxy-Piperidine-1-Carboxylic AcidIsopropyl Ester Intermediate (2)

To a stirred mixture of 4-hydroxypiperidine (53.8 g, 1.000 eq),triethylamine (71.8 g, 1.334 equivalents), and ethyl acetate (498.8 g)was added neat isopropyl chloroformate (78.0 g, 1.1966 equivalents) at arate sufficiently slow to maintain the reaction mixture temperature at10°-17° C. with reactor jacket cooling. After the addition had beencompleted, the reaction mixture was stirred at 20° C. for 18 hours. Thenwater (100 g) was added, and the resulting mixture was stirred for 15minutes before the phases were separated. The organic phase was washedwith two 100-gram-portions of 20 wt % aqueous NaCl by stirring for 15min at 150 rpm before separating the aqueous wash. After a final washwith water (100 g), the organic phase was concentrated by distillationon a rotary evaporator at reduced pressure to provide product (2) (91.1g, 92.0% yield) as light amber oil of 96.8% purity by GC. Distillationof this crude product at 117-120° C., 0.3-1.0 torr gave a 95.7% recoveryof product (2) as a colorless oil collected at 112°-119° C.

Example 3 Preparation of4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester intermediate (3)

4,6-Dichloro-5-methylpyrimidine (1) (2.4235 Kg, 1.000 equivalents) and4-hydroxypiperidine-1-carboxylic acid isopropyl ester (2) (2.8182 Kg,1.012 equivalents) were dissolved in tetrahydrofuran (THF, 25.0028 Kg),and the resulting solution was cooled to −15 to −10° C. To the coldsolution, potassium-tert-butoxide in tetrahydrofuran (1 M, 12.6051 Kg,0.9399 equivalents) was added at a rate sufficiently slow to maintainthe reaction mixture below 0° C. with reactor jacket cooling. Thereaction mixture was then stirred at about −5° C. for about 2 hoursbefore an additional portion of potassium-tert-butoxide intetrahydrofuran (1 M, 0.5692 Kg, 0.0424 equivalents) was added toachieve >97% conversion of the pyrimidine after an additional hour ofstirring at about −5° C. Most of the solvent was then removed bydistillation at 30-65° C., ≦80 torr. Addition of water (19.9681 Kg) tothe evaporation residue precipitated the product. Distillative removalof THF was then completed at 30-65° C., ≦80 torr, and the resultingstirred slurry was cooled to 0° C. for an hour. The solids were thencollected by suction filtration, washed with water (8.011 Kg, 4° C.),and vacuum dried to constant weight at 50° C., ≦40 torr to provideproduct (3) (4.491 Kg, 96.3% yield).

Example 4 Preparation of 2-fluoro-4-methanesulfonyl-phenol intermediate(4)

A stirred mixture of sodium methane sulfinic acid (51.0 g, 4.009equivalents), 4-bromo-2-fluorophenol (23.8 g, 1.000 equivalent),copper(I) trifluoromethanesulfonate benzene complex (6.28 g, 0.1001equivalents), N,N′-dimethylethylenediamine (DMEDA, 2.2 g, 0.2003equivalents), and dimethylsulfoxide (DMSO, 104 g) was heated undernitrogen at 130°-135° C. for 18 hours. Substantially all of the DMSOsolvent was then removed from the reaction mixture by rotary evaporationat 1 torr with a 120° C. oil bath. To the brown oily distillationresidue were added ethyl acetate (90 g) and water (100 g). After theresulting mixture had been heated and agitated to facilitate dissolutionof the reaction mixture in the two liquid phases, it was filteredthrough a coarse sintered glass filter funnel containing a Whatmanfilter paper disc and 30 g of Celite. Addition of concentrated aqueousHCl (20 g) to the filtrate lowered the pH of the aqueous phase to lessthan 3. The phases were separated, and the aqueous phase was extractedtwo more times with ethyl acetate (90 g each). The combined organicphases were extracted with three 100-gram-portions of 1 M aqueous NaOHto extract the sodium salt of the phenoxide product into the aqueousphase. The aqueous phases were combined, acidified with cooling andconcentrated aqueous HCl (40 g) to a pH less than 3, and then extractedwith four 90-gram-portions of ethyl acetate to return the product as thefree phenol to the organic phase. The organic phases were combined,dried over magnesium sulfate (15 grams), filtered, and concentrated byrotary evaporation at reduced pressure to provide product (4) (16.6 g,70% yield) as a clear orange to brown oil, which solidified on standing.

Example 5 Preparation of4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (5)

2-Fluoro-4-methanesulfonylphenol (4) (1.9863 Kg, 1.000 equivalent) and4-(6′-chloro-5′-methylpyrimidin-4′-yloxypiperidine)-1-carboxylic acidisopropyl ester (3) (3.3656 Kg, 1.027 equivalents) were dissolved indimethylsulfoxide (DMSO, 7.0160 Kg). To the resulting solution,tetrabutylammonium iodide promoter (2.5243 Kg, 0.6544 equivalents) andpotassium carbonate (1.7422 Kg, 1.207 equivalents) were added. Thereaction mixture was then stirred and heated at 130°-135° C. internaltemperature for about 24 hours, at which point conversion of phenol (4)to product (5) was >93%. The reaction mixture was then cooled to 50°-60°C. and, with the assistance of additional DMSO (0.5050 Kg), added towater (36.1206 Kg) maintained at 25°-35° C. throughout the addition.After the resulting slurry had been stirred at about 20° C. for severalhours, the precipitated solids were filtered, washed with water (8.1264Kg, 20° C.), and recrystallized from isopropyl alcohol (18.7195 Kg) bydissolution at 80° C. and cooling to 2° C. The recrystallization mixturewas stirred at 2° C. for two hours and then filtered. The filtered solidproduct was washed with a 2° C. mixture of isopropanol (6.9792 Kg) andwater (3.0329 Kg) and then recrystallized a second time from isopropanol(15.8899 Kg, 80° C.). After having been cooled to and stirred at 2° C.for two hours, the recrystallization mixture was filtered. The filteredsolid product was washed with a 2° C. mixture of isopropanol (5.8689 Kg)and water (2.590 Kg) and dried to constant weight at 50° C., ≦40 torr toprovide product (5) (3.8937 Kg, 79.75% yield).

Example 6 Preparation of4-[6-(2-fluoro-4-methanesulfonyl-phenoxy)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylicacid isopropyl ester (5)

2-Fluoro-4-methanesulfonyl-phenol (4) (1.33 g, 7.01 mmol) and4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acidisopropyl ester (3) (2.00 g, 6.39 mmol) were dissolved in DMSO (10 mL).To the resulting solution, potassium iodide (0.21 g, 1.27 mmol) andpotassium carbonate (0.97 g, 7.01 mmol) were added. The resultingmixture was heated to 130° C. and stirred overnight. The crude wascooled to room temperature, poured into ice water (150 mL) and stirredfor 2 h. The precipitate was filtered, washed twice with water (2×10 mL)and dried at 60° C. in a vacuum oven (2.74 g, 91%). The desired productwas recrystallized from isopropanol (10 mL) to afford 2.39 g of thetitle compound (80%).

Various modifications of the invention, in addition to those describedherein, will be apparent to those skilled in the art from the foregoingdescription. Such modifications are also intended to fall within thescope of the appended claims. Each reference cited in the presentapplication is incorporated herein by reference in its entirety.

1. A process for preparing a compound of Formula I:

wherein: X is N or CR⁷; Y is N or CR⁸; Z is C₁₋₅ acyl, C₁₋₅ acyloxy,C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆alkynyl, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, C₁₋₂ alkylamino, C₂₋₄ dialkylamino,carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₄₋₈ diacylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₂₋₆dialkylsulfonylamino, formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylcarboxamide, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,C₁₋₄ haloalkylthio, halogen, aryl, heteroaryl, heterocycloalkyl,hydroxyl, hydroxycarbamimidoyl, hydroxylamino, nitro, or tetrazolyl;wherein said C₁₋₈ alkyl, C₃₋₇ cycloalkyl, and heterocycloalkyl are eachoptionally substituted with 1, 2, 3 or 4 groups selected from C₁₋₅ acyl,C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylcarboxamide, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₂ alkylamino, C₂₋₄ dialkylamino,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, formyl, C₁₋₄ haloalkoxy,C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,halogen, hydroxyl, hydroxylamino, and nitro; R¹ is H, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl,C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino,carboxamide, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylsulfonamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, orhydroxyl; R² is —R²², —CR²³R²⁴C(O)—R²², —C(O)CR²³R²⁴—R²², —C(O)—R²²,—CR²³R²⁴C(O)NR²⁵—R²², —NR²⁵C(O)CR²³R²⁴—R²², —C(O)NR²³—R²²,—NR²³C(O)—R²², —C(O)O—R²², —OC(O)—R²², —C(S)—R²², —C(S)NR²³—R²²,—NR²³C(S)—R²², —C(S)O—R²², —OC(S)—R²², —CR²³R²⁴—R²², or —S(O)₂—R²²; R³is C₁₋₃ alkyl, C₁₋₄ alkoxy, carboxy, cyano, C₁₋₃ haloalkyl, or halogen;R⁴ is H, C₁₋₈ alkyl or C₃₋₇ cycloalkyl, wherein said C₁₋₈ alkyl isoptionally substituted with C₁₋₄ alkoxy, C₃₋₇ cycloalkyl, or heteroaryl;R₇ and R₈ are each, independently, H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino,carboxamide, cyano, C₃₋₇ cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylsulfonamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, orhydroxyl; R¹¹ is C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl, amino, arylsulfonyl,carbamimidoyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, guanidinyl, halogen,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, heterocycloalkyl,heterocycloalkyl-oxy, heterocycloalkylsulfonyl,heterocycloalkyl-carbonyl, heteroaryl, heteroarylcarbonyl, hydroxyl,nitro, C₄₋₇ oxo-cycloalkyl, phenoxy, phenyl, sulfonamide, sulfonic acid,or thiol; and wherein said C₁₋₅ acyl, C₁₋₆ acylsulfonamide, C₁₋₄ alkoxy,C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₆ alkylsulfonamide, C₁₋₄ alkylsulfonyl,C₁₋₄ alkylthio, arylsulfonyl, carbamimidoyl, C₂₋₆ dialkylamino,heterocycloalkyl, heterocycloalkyl-carbonyl, heteroaryl, phenoxy andphenyl are each optionally substituted with 1 to 5 substituents selectedindependently from C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy,C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄alkylthio, C₁₋₄ alkylureyl, carbo-C₁₋₆-alkoxy, carboxamide, carboxy,cyano, C₃₋₇ cycloalkyl, C₃₋₇ cycloalkyloxy, C₂₋₆ dialkylamino, C₂₋₆dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio,heteroaryl, heterocyclic, hydroxyl, nitro, phenyl, and phosphonooxy,wherein said C₁₋₇ alkyl and C₁₋₄ alkylcarboxamide are each optionallysubstituted with 1 to 5 substituents selected from C₁₋₄ alkoxy andhydroxy; R¹², R¹³, R¹⁴, and R¹⁵ are each, independently, H, C₁₋₅ acyl,C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₂₋₆dialkylcarboxamide, halogen, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄ haloalkylthio, hydroxyl,or nitro; R²² is H, C₁₋₈ alkyl, C₃₋₇ cycloalkyl, phenyl, heteroaryl, orheterocyclic each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₇ alkyl, C₁₋₄ alkylamino, C₁₋₄alkylcarboxamide, C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl,C₁₋₄ alkylureyl, amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano,C₃₋₇ cycloalkyl, C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆dialkylthiocarboxamide, C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkylthio, halogen,heteroaryl, heterocyclic, hydroxyl, hydroxylamino, nitro, phenyl,phenoxy, and sulfonic acid, wherein said C₁₋₇ alkyl, heteroaryl, phenyland phenoxy are each optionally substituted with 1 to 5 substituentsselected from the group consisting of C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylamino, C₁₋₄ alkylcarboxamide, C₁₋₄alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄ alkylureyl,amino, carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl,C₂₋₈ dialkylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide,C₂₋₆ dialkylsulfonamide, C₁₋₄ alkylthioureyl, C₁₋₄ haloalkoxy, C₁₋₄haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl, C₁₋₄haloalkyl, C₁₋₄ haloalkylthio, halogen, heterocyclic, hydroxyl,hydroxylamino, and nitro; R²³, R²⁴ and R²⁵ are each, independently, H orC₁₋₈ alkyl; n is 0 or 1; and m is 0, 1, 2,3, or 4; wherein said processcomprises reacting a compound of Formula II:

wherein L² is a leaving group, with compound of Formula III:

in the presence of a base and a salt, thereby forming the compound ofFormula I.
 2. The process of claim 1 wherein said salt is a tetra(C₁₋₈alkyl)ammonium salt is halide salt.
 3. The process of claim 1 whereinsaid salt is a tetrasubstituted ammonium iodide salt.
 4. The process ofclaim 1 wherein said salt is an alkali metal halide.
 5. The process ofclaim 1 wherein said salt is KI.
 6. The process of claim 1 wherein saidbase is an alkali metal amide, alkali metal hydride, alkali metalcarbonate, or an alkali metal hydrogencarbonate.
 7. The process of claim1 wherein said base is K₂CO₃.
 8. The process of claim 1 wherein saidreacting is carried out at elevated temperature.
 9. The process of claim1 wherein said reacting is carried out at a temperature of about 120 toabout 140° C.
 10. The process of claim 1 wherein said reacting iscarried out in a solvent.
 11. The process of claim 10 wherein saidsolvent comprises DMSO.
 12. The process of claim 1 wherein L² is halo.13. The process of claim 1 wherein L² is Cl.
 14. The process of claim 1wherein both X and Y are N.
 15. The process of claim 1 wherein Z is C₁₋₅acyl, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₂₋₆ alkynyl,formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, halogen, hydroxyl, or nitro.16. The process of claim 1 wherein Z is methyl.
 17. The process of claim1 wherein R¹ is H.
 18. The process of claim 1 wherein R² is —C(O)O—R²²and R²² is methyl, ethyl, or prop-1-yl, prop-2-yl.
 19. The process ofclaim 1 wherein R² is —C(O)O—R²² and R²² is prop-2-yl.
 20. The processof claim 1 wherein R⁴ is H.
 21. The process of claim 1 wherein n is 1.22. The process of claim 1 wherein m is
 0. 23. The process of claim 1wherein R¹¹ is C₁₋₄ alkylsulfonyl.
 24. The process of claim 1 whereinR¹¹ is methylsulfonyl.
 25. The process of claim 1 wherein R¹², R¹³, R¹⁴,and R¹⁵ are each, independently, H or halogen.
 26. The process of claim1 wherein R¹⁵ is F.
 27. The process of claim 1 wherein R¹¹ is C₁₋₄alkylsulfonyl; R¹², R¹³, and R¹⁴ are each H; and R¹⁵ is halogen.
 28. Theprocess of claim 1 wherein: X is N; Y is N; Z is methyl; R¹ is H; R² is—C(O)O—R²²; R⁴ is H; R¹¹ is methylsulfonyl; R¹², R¹³, and R¹⁴ are eachH; R¹⁵ is F; R²² is prop-2-yl; n is 1; and m is
 0. 29. The process ofclaim 1 wherein said compound of Formula II is prepared by: a) combininga compound of Formula IV:

with a compound of Formula V:

wherein L¹ is a leaving group, to form a mixture; and b) adding a baseto said mixture, thereby forming the compound of Formula II.
 30. Theprocess of claim 29 wherein said base is C₁₋₆alkoxide salt, alkali metalamide, alkali metal hydride, alkali metal carbonate, or an alkali metalhydrogencarbonate.
 31. The process of claim 29 wherein said base ispotassium t-butoxide.
 32. The process of claim 29 wherein said combiningand adding are carried out in a solvent.
 33. The process of claim 32wherein said solvent comprises tetrahydrofuran.
 34. The process of claim29 wherein said adding is carried out at a temperature below about 10°C.
 35. The process of claim 29 wherein L¹ is halo.
 36. The process ofclaim 29 wherein L¹ is Cl.
 37. A process for preparing a compound ofFormula II:

wherein: X is N or CR⁷; Y is Nor CR⁸; Z is C₁₋₅ acyl, C₁₋₅ acyloxy, C₂₋₆alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl,C₁₋₄ alkylthiocarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl,C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylthioureyl, C₁₋₄alkylureyl, amino, C₁₋₂ alkylamino, C₂₋₄ dialkylamino, carbamimidoyl,carbo-C₁₋₆-alkoxy, carboxamide, carboxy, cyano, C₃₋₇ cycloalkyl, C₄₋₈diacylamino, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylthiocarboxamide, C₂₋₆dialkylsulfonamide, C₂₋₆ dialkylsulfonylamino, formyl, C₁₋₄ haloalkoxy,C₁₋₄ haloalkyl, C₁₋₄ haloalkylcarboxamide, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, halogen, aryl, heteroaryl,heterocycloalkyl, hydroxyl, hydroxycarbamimidoyl, hydroxylamino, nitro,or tetrazolyl; wherein said C₁₋₈ alkyl, C₃₋₇ cycloalkyl, andheterocycloalkyl are each optionally substituted with 1, 2, 3 or 4groups selected from C₁₋₅ acyl, C₁₋₅ acyloxy, C₁₋₄ alkoxy, C₁₋₇ alkyl,C₁₋₄ alkylcarboxamide, C₁₋₄ alkylsulfonamide, C₁₋₄ alkylsulfinyl, C₁₋₄alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl, amino, C₁₋₂ alkylamino,C₂₋₄ dialkylamino, carbo-C₁₋₁₆-alkoxy, carboxamide, carboxy, cyano,formyl, C₁₋₄ haloalkoxy, C₁₋₄ haloalkylsulfinyl, C₁₋₄ haloalkylsulfonyl,C₁₋₄ haloalkylthio, halogen, hydroxyl, hydroxylamino, and nitro; R¹ isH, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl, C₁₋₄alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, carboxamide, cyano, C₃₋₇cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, or hydroxyl; R² is —R²²,—CR²³R²⁴C(O)—R²², —C(O)CR²³R²⁴—R²², —C(O)—R²², —CR²³R²⁴C(O)NR²⁵—R²²,—NR²⁵C(O)CR²³R²⁴—R²², —C(O)NR²³—R²², —NR²³C(O)—R²², —C(O)O—R²²,—OC(O)—R²², —C(S)—R²², —C(S)NR²³—R²², —NR²³C(S)—R²², —C(S)O—R²²,—OC(S)—R²², —CR²³R²⁴—R²², or —S(O)₂—R²²; R³ is C₁₋₃ alkyl, C₁₋₄ alkoxy,carboxy, cyano, C₁₋₃ haloalkyl, or halogen; R⁴ is H, C₁₋₈ alkyl or C₃₋₇cycloalkyl, wherein said C₁₋₈ alkyl is optionally substituted with C₁₋₄alkoxy, C₃₋₇ cycloalkyl, or heteroaryl; R₇ and R₈ are each,independently, H, C₁₋₅ acyloxy, C₂₋₆ alkenyl, C₁₋₄ alkoxy, C₁₋₈ alkyl,C₁₋₄ alkylcarboxamide, C₂₋₆ alkynyl, C₁₋₄ alkylsulfonamide, C₁₋₄alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₄ alkylthio, C₁₋₄ alkylureyl,amino, C₁₋₄ alkylamino, C₂₋₈ dialkylamino, carboxamide, cyano, C₃₋₇cycloalkyl, C₂₋₆ dialkylcarboxamide, C₂₋₆ dialkylsulfonamide, halogen,C₁₋₄ haloalkoxy, C₁₋₄ haloalkyl, C₁₋₄ haloalkylsulfinyl, C₁₋₄haloalkylsulfonyl, C₁₋₄ haloalkylthio, or hydroxyl; n is 0 or 1; m is 0,1, 2, 3, or 4; and L² is a leaving group; comprising: a) combining acompound of Formula IV:

with a compound of Formula V:

wherein L¹ is a leaving group, to form a mixture; and b) adding a baseto said mixture while maintaining the temperature of the mixture belowabout room temperature, thereby forming said compound of Formula II. 38.The process of claim 37 wherein said adding is carried out whilemaintaining the temperature of the mixture below about 0° C.
 39. Theprocess of claim 37 wherein said base is C₁₋₆ alkoxide salt, alkalimetal amide, alkali metal hydride, alkali metal carbonate, or an alkalimetal hydrogencarbonate.
 40. The process of claim 37 wherein said baseis a potassium t-butoxide.
 41. The process of claim 37 wherein saidcombining and adding are carried out in a solvent.
 42. The process ofclaim 41 wherein said solvent comprises tetrahydrofuran.
 43. The processof claim 37 wherein said mixture is cooled to a temperature of about −15to about −10° C. prior to said adding.
 44. The process of claim 37wherein L¹ is halo.
 45. The process of claim 37 wherein L¹ is Cl.